ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1730C>T (p.Ser577Leu) (rs56185292)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656864 SCV000149374 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1730C>T at the cDNA level, p.Ser577Leu (S577L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant, also defined as MLH1 1007C>T (Ser336Leu) using alternate nomenclature, was observed in at least three individuals undergoing hereditary cancer risk assessment for Lynch syndrome (Chao 2008, Lagerstedt-Robinson 2016). MLH1 Ser577Leu was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MLH1 Ser577Leu was observed at an allele frequency of 0.06% (11/18852) in individuals of East Asian ancestry in large population cohorts (Lek 2016). MLH1 Ser577Leu is located within the regions of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Ser577Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115465 SCV000184371 benign Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing No disease association in appropriately sized case-control study(ies);Other data supporting benign classification;Structural Evidence
Invitae RCV000226023 SCV000284028 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 577 of the MLH1 protein (p.Ser577Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs56185292, ExAC 0.07%). This variant has been observed in individuals with breast cancer, with colorectal cancer, and with pancreatic cancer (PMID: 27601186, 28767289, 25186627). ClinVar contains an entry for this variant (Variation ID: 127619). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5
Counsyl RCV000411289 SCV000488812 uncertain significance Lynch syndrome II 2016-06-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115465 SCV000537587 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-26 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 32659497, 32959997) and an unaffected individual in a pancreatic cancer case-control study (PMID: 32980694). This variant has been identified in 17/282594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121362 SCV000592418 uncertain significance not specified 2015-05-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121362 SCV000601362 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515241 SCV000611399 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2017-05-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411289 SCV001310411 uncertain significance Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656864 SCV001371043 uncertain significance not provided 2020-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121362 SCV001572382 uncertain significance not specified 2021-04-01 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1730C>T (p.Ser577Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located close to a canonical splice site, therefore could affect splicing: 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251202 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is approximately equal to the maximum expected for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00071), suggesting that the variant could be a benign polymorphism. The variant, c.1730C>T, has been reported in the literature in individuals affected with colorectal cancer and other tumor phenotypes that belong to the Lynch Syndrome tumor spectrum (Chao_2008, Lagerstedt-Robinson_2016, Toh_2018, Li_2020, Jiang_2020, Shindo_2017). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The variant has been also reported in the literature in multiple individuals affected with Breast Cancer (e.g. Tung_2015, Wang_2019). However, a recent large-scale Breast Cancer study reported the variant in 13/60466 BrC cases and 13/53461 controls, i.e. with a calculated odds ratio of 0.88, which suggests that this variant is not associated with a risk for Breast Cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=9), or benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
ITMI RCV000121362 SCV000085543 not provided not specified 2013-09-19 no assertion provided reference population

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